小柯机器人

非肽激动剂激活GLP-1受体，这一成果由澳大利亚莫纳什大学Denise Wootten、Patrick M. Sexton和日本东京大学Radostin Danev课题组合作取得。该研究成果在线发表在2020年1月8日出版的国际学术期刊《自然》上。

研究人员解析了可与胰高血糖素样肽1（GLP-1）受体结合的非肽激动剂TT-OAD2的结构。该结构揭示了一个未知的非肽激动剂结合口袋，其中细胞外环和跨膜螺旋的重组不依赖深跨膜结构域口袋中的直接配体相互作用。不同于肽激动剂，TT-OAD2表现出偏向激活作用类似于G蛋白活化动力学和信号传导。在该结构内，TT-OAD2突出到受体核心之外，与脂质或去垢剂相互作用，可能为该类化合物临床疗效的独特激活动力学提供了解释。这项工作改变了人们对驱动B类受体激活机制的认知。

据了解，B类G蛋白偶联受体是治疗包括糖尿病和肥胖症在内慢性疾病的主要靶点。活性受体结构揭示肽激动剂深入受体核心内，导致细胞外环和顶部跨膜螺旋的向外运动、跨膜螺旋的向内运动、细胞外环的重组和细胞膜的向外运动。细胞内跨膜螺旋的向外移动导致G蛋白相互作用和激活。

附：英文原文

Title: Activation of the GLP-1 receptor by a non-peptidic agonist

Author: Peishen Zhao, Yi-Lynn Liang, Matthew J. Belousoff, Giuseppe Deganutti, Madeleine M. Fletcher, Francis S. Willard, Michael G. Bell, Michael E. Christe, Kyle W. Sloop, Asuka Inoue, Tin T. Truong, Lachlan Clydesdale, Sebastian G. B. Furness, Arthur Christopoulos, Ming-Wei Wang, Laurence J. Miller, Christopher A. Reynolds, Radostin Danev, Patrick M. Sexton, Denise Wootten

Issue&Volume: 2020-01-08

Abstract: Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity1. Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation2,3,4,5,6. Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors.

DOI: 10.1038/s41586-019-1902-z

Source: https://www.nature.com/articles/s41586-019-1902-z

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